It is important to evaluate schizophrenia in its early stages in order to identify brain sites that are affected, such that causes of illness may be better understood and appropriate preventive interventions developed. A major research goal has been to use magnetic resonance imaging (MRI) to identify areas of brain abnormality which would inform our knowledge as to the mechanisms underlying the early evolution and emergence of schizophrenia. Our group identified a promising imaging biomarker using a high-resolution variant of functional MRI using gadolinium contrast- increased basal function in hippocampal subregions, which was associated with schizophrenia itself, related to the severity of positive psychotic symptoms across illness stages such as delusions, and predicted progression to psychosis from a prodromal or clinical high-risk state in a small cohort (Schobel, Lewandowski et al. 2009) Importantly, these findings to date are based upon a relatively small cohort of subjects, 27 patients with schizophrenia, 27 patients who are at high clinical risk for psychosis, and 24 comparison subjects. We aim to build upon our previous published study by expanding the cohort of schizophrenia and patients at clinical risk for psychosis to test the predictive value of the putative marker, and include longitudinal assessment of brain function and structure. The significance of this proposal is to definitively test the utility of using a high-resolution fMRI variant to detect the earliest stages of schizophrenia, to test the utility of using a lower-resolution non- invasive fMRI variant to detect the earliest stages of schizophrenia, and to clarify the relationship between abnormal brain function and structure in its onset. If the proposed aims are achieved, our diagnostic capabilities in prodromal stages of disease will be enhanced as well as our understanding of the pathophysiology of emergent psychotic illness, both of which are key to developing preventative interventions in an effort to reduce the significant morbidity of schizophrenia and related psychotic disorders. PUBLIC HEALTH RELEVANCE: Schizophrenia, like all diseases of the brain, targets specific brain regions more than others. Pinpointing these targeted regions with brain imaging is challenging but important, for diagnostic purposes and for understanding mechanisms of disease. In this application we will use two variants of functional brain imaging that can detect disease-associated dysfunction in small regions of the brain and apply this to patients at clinical risk for psychosis who are followed prospectively for clinical and brain imaging outcomes. The main project goal is to definitively test the hypothesis of hippocampal hyperfunction as a pathogenic driver in schizophrenia and related disorders.